1. Field of the Invention
This invention relates to the use of tenidap and the pharmaceutically-acceptable base salts thereof to inhibit activation of collagenase in a mammal. This invention also relates to the use of tenidap and the pharmaceutically-acceptable base salts thereof for treating collagenase mediated disorders and diseases such as bone resorption disorders, corneal ulceration, periodontal disease, inflammatory diseases and wounds of the skin and burns in a mammal. Further, this invention relates to the use of tenidap and the pharmaceutically-acceptable base salts thereof to inhibit the activity of myeloperoxidase in a mammal. The methods of this invention comprise administering an effective amount of tenidap or salts thereof to such a mammal.
2. General Background
Tenidap, 5-chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-indole-1-carboxamide, has the structural formula ##STR1## Tenidap and the pharmaceutically-acceptable base salts thereof, among other 3-substituted-2-oxindole-1-carboxamides, are disclosed and claimed in U.S. Pat. No. 4,556,672 which is assigned to the assignee hereof. That patent discloses that those compounds, in addition to being useful as antiinflammatory and analgesic agents, are inhibitors of both the cyclooxygenase (CO) and lipoxygenase (LO) enzymes. The teachings thereof are incorporated herein by reference.
The use of tenidap and its pharmaceutically-accceptable base salts, among certain other 3-substituted-2-oxindole-1-carboxamides, to inhibit interleukin-1 biosynthesis in a mammal and to treat interleukin-1 mediated disorders and dysfunctions is disclosed in U.S. Pat. No. 4,861,794 which is assigned to the assignee hereof.
U.S. Pat. No. 4,853,409, assigned to the assignee hereof, discloses the use of tenidap and its pharmaceutically-acceptable base salts, among certain other 3-substituted-2-oxindole-1-carboxamides, to suppress T-cell function in a mammal and to treat T-cell mediated autoimmune disorders of the systemic or organ specific type.
An anhydrous, crystalline form of the sodium salt of tenidap is disclosed in European Patent Application 277,738 which has been filed in the name of the assignee hereof.
Collagenase is a protease which is stored within neutrophil specific granules in a latent form. [Hasty, K.A., et al., J. Biol. Chem. 261:5645-5650 (1986) and Hasty, K.A., et al., J. Biol. Chem. 262:10048-10052 (1987).]Collagenase, in its activated form, mediates a variety of disorders and diseases in a mammal. These disorders and diseases include, but are not limited to, bone resorption disorders such as osteoporosis and metastatic bone cancer, corneal ulceration, periodontal disease, inflammatory joint disease, inflammatory diseases and wounds of the skin and burns. [Harris, E.D., et al., NEJM 291:605-609 (1974) and Harris, E.D., et al., NEJM 291:652-660 (1974).]Collagenase can be activated from its latent form by hypochlorous acid. [Weiss, S.J., et al., Science 227:747-749 (1985).]The enzyme myeloperoxidase converts hydrogen peroxide, itself the dismutased product of superoxide radicals, into hypochlorous acid. Once activated, collagenase is capable of irreversibly cleaving collagen of types 1, 2 and 3. [Hasty, D.A., et al., J. Biol. Chem. 262:10048-10052 (1987).]
It has been reported that certain gold compounds can interfere with activated collagenase, but only in the presence of organomercurials. [Mallya, S.K., et al., J. Biol. Chem. 264:1594-1601 (1989) and Mallya, S.K. et al., Biochem. Biophys. Res. Comm. 144:101-108 (1987).]Further, penicillamine has been reported to scavenge hypochlorite and inhibit its formation by myeloperoxidase. [Cuperus, R.A., et al., Arthritis
Rheum. 28:1228-1233 (1985).]
However, until the invention herein, there was no report of use or intent to use tenidap or the salts thereof to inhibit the activation of collagenase and to treat collagenase mediated disorders and diseases such as bone resorption disorders, corneal ulceration, periodontal disease, inflammatory diseases of the skin and burns with tenidap nor any appreciation of its role in such treatments. Further, there was no report of use or intent to use tenidap or the salts thereof to inhibit the activity of myeloperoxidase with tenidap nor any appreciation of its ability to inhibit myeloperoxidase in a mammal.